Recent studies indicate that over half of patients with HIV/AIDS take complementary and alternative medicines (CAM) along with their prescription anti-HIV drugs. Despite this, little is known about the pharmacology, pharmacokinetics, or pharmacodynamics of CAMs, or how they interact with standard anti-HIV regimens. Adverse interactions may lead to profound clinical consequences, the development of resistance, and failure of antiretroviral therapy. Many patients on highly active anti-retroviral therapy (HAART) regimens use olive leaf extract (OLE) to lessen the side effects of HAART, and for its own anti-HIV effects. There is therefore an urgent need to understand the anti-HIV effects of OLE and how it interacts with HAART medications. We propose three specific aims: First, to use rigorous drug interaction studies to define whether the effects of OLE are additive, synergistic, or antagonistic with 3TC, AZT, and IND, a standard triple-drug HAART regimen. Second, to define the effects of OLE on three specific steps in the viral life cycle: viral binding, reverse transcription, and protease processing of viral proteins. Third, to test the in vivo pharmacokinetics of OLE, and whether OLE affects the intracellular accumulation of anti-HIV drugs by effects on efflux and influx drug transport systems. We propose to use well-characterized OLE preparations standardized by LC-MS. Our long term goals are to understand the molecular mechanisms by which OLE exerts anti-HIV effects, and to promote synergistic effects while avoiding antagonistic interactions during anti-HIV therapy. We hope that this information will provide an important knowledge base for anti-HIV therapy of OLE alone or in combination with HAART, as well as contribute to our understanding of viral pathogenesis. [unreadable] [unreadable] [unreadable]